Clinical significance of NOTCH1 intracellular cytoplasmic domain translocation into the nucleus in gastric cancer.
Clinical significance of NOTCH1 intracellular cytoplasmic domain translocation into the nucleus in gastric cancer.
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DOI：
10.3892/br.2016.723
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发表时间：
2016-09
影响因子：
2.3
通讯作者：
S. Saito;H. Ishiguro;M. Kimura;R. Ogawa;H. Miyai;Tatsuya Tanaka;K. Mizoguchi;H. Takeyama
中科院分区：
文献类型：
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作者：
S. Saito;H. Ishiguro;M. Kimura;R. Ogawa;H. Miyai;Tatsuya Tanaka;K. Mizoguchi;H. Takeyama
最近的研究表明，Notch信号通路在各种类型的恶性肿瘤中的组成性激活。然而，目前还不清楚这种信号通路是否在胃癌中被激活。在本研究中，目的是通过研究胃癌患者组织样本中Notch相关蛋白的亚细胞定位来研究Notch信号在胃癌中的作用。样本来自115名胃癌患者，这些患者在名古屋市立大学医学研究生院消化外科接受手术，术前未接受化疗或放疗。随后，研究了NOTCH 1胞内胞质结构域（NICD）易位到细胞核中（通过免疫染色测量）与胃癌患者手术后存活率之间的相关性。结合患者的临床病理特征分析结果，并确定这些结果对患者预后的影响。NICD核定位与肿瘤状态（T因子）、淋巴结状态（N因子）、病理分期及分化程度等临床病理特征相关。NICD核定位与年龄、性别、肿瘤部位、静脉侵犯或淋巴侵犯无明显相关性。与NICD阳性癌细胞核<30%的患者相比，NICD阳性癌细胞核>30%的患者（如免疫染色所示）手术后生存期显著缩短（对数秩检验，P=0.0194）。单因素分析显示，在所检查的临床病理因素中，T因素[危险率（RR）=10.870; P=0.0016]、N因素（RR=41.667; P=0.0003），淋巴管浸润（RR=13.158; P=0.0125）、静脉侵犯（RR=25.000; P= 0.0019）和NICD核移位（RR=3.937; P=0.0312）均为有统计学意义的预后因素。然而，多因素分析显示，NICD易位到细胞核是不是独立相关的胃癌患者的预后不良。提示NOTCH 1在胃癌中起癌基因的作用。因此，NICD向细胞核内的转位可能成为胃癌治疗的靶点。
Recent studies have shown constitutive activation of the Notch signaling pathway in various types of malignancies. However, it remains unclear whether this signaling pathway is activated in gastric cancer. In the present study, the aim was to investigate the role of Notch signaling in gastric cancer by investigating the subcellular localization of Notch-associated proteins in tissue samples from gastric cancer patients. Samples were obtained from 115 gastric cancer patients who had undergone surgery at the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science without pre-operative chemotherapy or radiation. Subsequently the correlation between translocation of NOTCH1 intracellular cytoplasmic domain (NICD) into the nucleus (as measured by immunostaining) and survival in gastric cancer patients after surgery was investigated. The results were analyzed in reference to the patients' clinicopathological characteristics and the effects of these results on patient prognosis were determined. Significant correlations were observed between NICD nuclear localization and clinicopathological characteristics, such as tumor status (T factor), lymph node status (N factor), pathological stage and differentiation status. No significant correlations were observed between NICD nuclear localization and age, gender, tumor location, vein invasion or lymphatic invasion. Patients with >30% of cancer cell nuclei positively stained for NICD (as revealed by immunostaining) were associated with a significantly shorter survival following surgery than patients with <30% NICD-positive cancer cell nuclei (log-rank test, P=0.0194). Univariate analysis revealed that among the clinicopathological factors examined, T factor [risk rate (RR)=10.870; P=0.0016], N factor (RR=41.667; P=0.0003), lymphatic invasion (RR=13.158; P=0.0125), vein invasion (RR=25.000; P= 0.0019) and translocation of NICD to the nucleus (RR=3.937; P=0.0312) were all identified to be statistically significant prognostic factors. However, multivariate analysis revealed that translocation of NICD to the nucleus was not independently associated with an unfavourable prognosis in patients with gastric cancer. The present results suggest that NOTCH1 acts as an oncogene in gastric cancer. It is hypothesized that translocation of NICD into the nucleus may be used as a therapeutic target in gastric cancer.